Abstract: Hearing loss associated with congenital human cytomegalovirus (HCMV) infection, a relatively frequent perinatal infection, accounts for nearly 25% of all causes of hearing loss in infants and children in the US. The mechanisms of disease caused by infection of the inner ear by this large herpesvirus are unknown, primarily because of hurdles inherent in the investigation of the inner ear in humans. We have developed an informative murine model of hearing loss in which newborn mice are infected peripherally and not intracranially with the closely related murine CMV. In this model, about 30-50% of infected mice develop sensorineural hearing loss and a significant number of mice with hearing loss exhibit progression in hearing loss, a clinically important feature of hearing loss in infants with HCMV associated hearing loss. Our findings strongly argue that virus-induced inflammation and not direct viral cytopathology is responsible for hearing loss and progressive hearing loss in this model. Our studies will explore this hypothesis and define mechanisms of virus-induced inflammation that are responsible for damage of the developing auditory system and hearing loss in animals with CMV infection of the inner ear. Results from these studies will guide investigation into mechanisms of hearing loss in infants and children with HCMV associated hearing loss and identify therapeutic approaches that can be translated into treatment and prevention of hearing loss in CMV infected infants.